Taxifolin Possesses Anti‑Cancer Activity on the 7,12‑Dimethylbenz(a)anthracene‑Induced Breast Cancer in the Sprague Dawley Rats by Remodeling Nuclear Factor Erythroid 2‑ Kelch‑Like ECH‑Associated Protein 1‑Heme Oxygenase 1 and Anti‑Oxidant Pathways

Background: In mammary cancer, alterations in various gene expressions and signaling pathways occurs due to the secondary effects of oxidative stress that facilitates cancer by causing genomic instability and mutagenic alterations. Several phenolic compounds are active against various malignancies. Taxifolin (TAX) exhibits diverse bioactivity profile that also contributes toward its anticancer efficacy. Objective: The present study has been designed for estimation of the anticancer potential of TAX on 7,12‑dimethylbenz(a)anthracene (DMBA)‑induced breast cancer in Sprague Dawley (SD) rats. Materials and Methods: Molecular docking analysis of Kelch‑like ECH‑associated protein 1 (Keap‑1) and heme oxygenase‑1 (HO‑1) was carried out using Maestro tool to rationalize the activity of TAX based on their binding potential. This was followed by DMBA administration in air pouch to induce mammary cancer in female SD rats (50–55 days old). After 90 days of cancer induction, the chemotherapeutic potential of TAX was evaluated by the administration of TAX at doses 10, 20, and 40 mg/kg/day. Besides this, the effect of TAX on Keap‑1‑nuclear factor erythroid‑2 (Nrf‑2) pathway associated with HO‑1 and NADPH:quinoneoxidoreductase 1 (NQO1) expressions and their effect on the anti‑oxidative and anti‑proliferative activity was also evaluated through immunofluorescence analysis, real‑time quantitative polymerase chain reaction, and biochemical estimations. Results: TAX revealed protective effect against lipid peroxidation, enzymatic (superoxide dismutase [SOD], manganese‑containing SOD, copper‑ and zinc‑containing SOD, catalase, and glutathione peroxidase), and nonenzymatic (reduced glutathione, α‑tocopherol, and ascorbic acid) anti‑oxidative markers in serum, liver, kidney, and breast tissue of both control and experimental groups. The study revealed upregulation of protective Nrf‑2, HO‑1, and NQO1 expressions with consequent suppression in Keap‑1 mRNA expression. Conclusion: This study revealed the potency of TAX in the inhibition of mammary carcinogenesis through Nrf‑2‑Keap‑1‑HO‑1 and antioxidant pathway.